Sounding the alarm and putting out the fire: new mechanistic insights into inflammation triggered by invasive infection

Speaker

Summary

The Lieberman laboratory has been in the forefront of developing RNAi-based therapeutics and using RNAi for genome-wide screening. They were the first to demonstrate that siRNAs could protect mice from disease. They developed methods to harness RNAi to inhibit herpes and HIV transmission in animal models. They have developed strategies for cell-targeted RNAi to treat viral infection, immune disease, and cancer. They are currently investigating tumor-targeted siRNAs for immunotherapy to activate tumor expression of neoantigens and avoid autoimmune side effects of checkpoint inhibitors. They also investigate the role of endogenous microRNAs and lncRNAs in regulating cell differentiation and cancer.

More specifically, Dr. Lieberman and her colleagues study cytotoxic T lymphocytes and their role in infection and tumor immunity. Her lab investigates the molecular pathways used by killer lymphocytes and their cytotoxic granule proteases, called granzymes, and pore-forming proteins, perforin and granulysin, to induce programmed cell death. They have defined a caspase-independent programmed cell death pathway activated by granzyme A. Recent work has identified an unexpected role for granzymes and granulysin in protection against bacteria and parasites. They recently uncovered the molecular basis for inflammatory cell death (pyroptosis) triggered by invasive bacteria and other danger signals and found that it is due to membrane pore formation by an inflammatory caspase-cleaved protein, gasdermin D. This mechanism also directly kills the bacteria that trigger the inflammasome. Current work focuses on innate and adaptive immune responses to invasive pathogens, including bacteria, malaria and other parasites, and fungi, including the role of decidual NK cells in protection against infection in pregnancy.